Our work is concerned with identifying the factor involved in the regulation of pyrimidine degradation by the liver. The effects of fasting, dietary alterations, and various chemotherapy regimens on the disposition of 5-fluorouracil (5-FU) by the isolated perfused rat liver are being investigated. The disappearance of pyrimidines from the perfusate of isolated perfused liver follows apparent Michaelis-Menten kinetics. The apparent Km and Vmax for 5-FU disappearance are greater than the same parameters forboth uracil and thymine which are degraded by the same enzymes. The production of 14CO2 from the 2-position of the pyrimidine ring is coorelated with 5-FU disappearance from the perfusate. This result suggests that the rate of appearance of 14CO2 in the expired air of animals might be an index of the degradation rate of pyrimidines after drug labelled in the 2-position of the pyrimidine ring is administered. Fasting and repeated doses of fluorouracil appeared to inhibit hepatic pyrimidine degradation. The amount of inhibition in both cases seems to the amount of weight loss. The mechanism by which this occurs has not been elucidated.